[unreadable] Acute cardiovascular disease (CVD) events are preceded by asymptomatic atherosclerotic changes in [unreadable] vascular function and structure (vascular remodeling [VR]). The RANK (receptor activator of nuclear factor kappa-B), RANK ligand, and osteoprotegerin pathway (RRO) has emerged as a possible fundamental pathway in the development of atherosclerotic VR and CVD. We hypothesize that population variation in the RRO pathway influences the risk of developing atherosclerotic VR and/or clinical CVD. The proposed research has 3 specific aims: (1) to define the set of cis-acting and trans-acting polymorphisms that influence the expression of RRO genes in lymphocytes and the serum level of RANKL and OPG biomarkers in humans; (2) to determine if genetic variation in the RRO pathway is associated with intermediate VR phenotypes and/or clinical CVD; and (3) to determine if biomarker level variation in the RRO pathway is associated with intermediate VR phenotypes and/or clinical CVD. The 3 aims will be addressed in a cellular model system (B lymphocytes from individuals genotyped in the International Haplotype Map project) and in humans (a large community-based cohort [Framingham Heart Study]) and a cohort of premature acute coronary syndrome cases collected at Massachusetts General Hospital [MGH]). The goal of this research is to clarify the role of the RRO pathway in contributing to the development of CVD. Insights from this research may lead to new targets for prevention, risk stratification, and therapy of CVD. The candidate is a cardiology investigator at MGH and an Instructor in Medicine at Harvard Medical School. Long-term, he seeks to define the contribution of genes to the risk of CVD and integrate these insights with blood biomarkers and subclinical disease measures to advance our ability to predict and prevent CVD. He has assembled a team of investigators from three scientific institutions - MGH, Framingham Heart Study, and Broad Institute - to guide his training. By successfully completing this research and associated educational activities, the candidate will obtain a deeper understanding of and a greater sophistication with genomics and statistical methods setting the stage for an independent career in cardiovascular genetic epidemiology. In addition, the candidate will be well positioned to transition from conducting pathway-based investigation to genome-wide association studies for cardiovascular phenotypes. [unreadable] [unreadable]